1. Introduction
The absolute and relative risks of mortality from infections in hemodialysis patients have greatly increased due to their immunocompromised state, frequent exposure to the hospital environment, and tunneled catheters that allow the formation of biofilms [
1,
2]. Infection accounts for 12% to 36% of mortality in hemodialysis patients and is second only to cardiovascular disease as a cause of death [
3,
4]. The most common species detected in hemodialysis patients are
Staphylococcus, including methicillin-resistant
Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative
Staphylococci (MRCNS), which account for 69.1% of these microbes [
5]. Moreover, it has been reported that infection mortality due to MRSA and MRCNS is 63.2% [
5]. Therefore, appropriate antibiotic selection for infections due to MRSA and MRCNS in hemodialysis patients is an important factor for improving mortality.
Current guidelines recommend the use of vancomycin or daptomycin for the empirical treatment of MRSA infections in hemodialysis patients [
6]. Although vancomycin is still considered the first-line treatment for MRSA infections owing to its bactericidal action, serious concerns regarding its safety profile, such as nephrotoxicity, have been raised [
7]. However, this may not be a critical issue for hemodialysis patients. Moreover, very few studies have investigated the effectiveness of vancomycin versus daptomycin in patients undergoing hemodialysis. Hence, we retrospectively evaluated the effectiveness and safety of vancomycin and daptomycin in hemodialysis patients.
3. Discussion
To the best of our knowledge, this is the first study to compare the effectiveness and safety of vancomycin and daptomycin in patients undergoing hemodialysis. In our study, the vancomycin treatment improved mortality without significant adverse events compared with the daptomycin treatment. Moreover, the loading dose, especially that of daptomycin, was one of the covariates related to mortality, which was reduced to 8.3%. Therefore, vancomycin remains as the first-line treatment, while a loading dose of daptomycin may be beneficial in hemodialysis patients.
To date, studies in various populations have investigated and compared the effectiveness and safety of vancomycin and daptomycin [
8,
9]. A recent meta-analysis indicated that daptomycin was better tolerated than vancomycin in the treatment of MRSA infections without lung involvement [
10]. On the other hand, a systematic review of hemodialysis patients reported that there were no studies evaluating the incidence of adverse events attributable to vancomycin [
11]. Japanese studies, including the present one, have shown that hemodialysis patients do not frequently develop adverse events caused by vancomycin [
12]. These observations highlight the higher tolerability of vancomycin in hemodialysis patients than in those with residual renal function.
In a meta-analysis, the risk of mortality failed to show a statistically significant difference between vancomycin and daptomycin for the treatment of MRSA infections in all patients [
10]. However, it has been reported that the clinical failure rate of patients with impaired renal function is lower with vancomycin than with daptomycin [
13,
14]. Moreover, the present study of hemodialysis patients indicated that vancomycin significantly reduced mortality as compared to daptomycin. Therefore, vancomycin may be more effective than daptomycin in patients with impaired renal function, especially hemodialysis patients. In contrast, there were no significant differences in the clinical and microbiological effectiveness between vancomycin and daptomycin treatments. Moreover, the levels of inflammatory markers before treatment were not significantly different between the two groups. Therefore, the reduction in mortality may be associated with an improvement in the early clinical response. However, the present study did not design to measure the blood concentration of daptomycin even though daptomycin requires a considerable time to achieve steady-state concentrations because of half-life in hemodialysis patients. Further well-designed studies are needed to validate the effectiveness and safety of vancomycin versus daptomycin. Moreover, although caution is advised since the benefits of vancomycin for hemodialysis patients may depend on the MIC, the present as well as other studies [
15,
16] have found no association between antibiotic treatment and mortality.
A loading dose regimen has been recommended to rapidly reach an effective therapeutic concentration as well as to optimize pharmacokinetic and pharmacodynamic indicators [
17,
18,
19,
20]. However, a recent meta-analysis reported that a loading dose of vancomycin did not reduce mortality or improve microbiological effectiveness [
21]. In contrast, we previously found in an in vivo study that a loading dose of daptomycin exhibited a higher microbiological activity [
22]. Retrospective studies showed that similar treatments also improved clinical symptoms at an early stage [
17,
23]. In the present study, daptomycin treatment without the loading dose showed a significantly higher mortality than the vancomycin treatment (
p < 0.01), while the mortality in the patients receiving daptomycin treatment with the loading dose was equivalent with those of the vancomycin treatment (
p = 0.52). Therefore, daptomycin treatment with the loading dose appears to be effective for hemodialysis patients. However, further large-scale studies are needed since the sample size is limited.
Recent practical guideline has recommended a high dose of daptomycin [
6]. However, the present retrospective study did not include patients receiving a high dose of daptomycin since previous studies of patients with renal impairment reported that the high dose was associated with a high incidence of creatinine kinase elevation [
24]. Therefore, further studies to compare a normal dose with a high dose of daptomycin are needed to validate the effectiveness of a high dose of daptomycin.
Several considerations should be made when interpreting our results. First, this was a non-randomized, single-center, retrospective study. We were unable to investigate the degree of disease severity owing to a lack of data. Selection bias could have been present, and missing data may have influenced the results. Thirty-four patients were treated with daptomycin throughout the study period, and patients receiving a loading dose of daptomycin were 12. The quality of the study is limited by its small sample size. It should be noted that patients, in whom MRSA, MRCNS, or E. faecium were detected, were included in our study. Although we were not able to evaluate the microbiological effectiveness in 22.4% of the patients, more detailed microbiological data regarding the MIC values were reported.
4. Patients and Methods
4.1. Patient Population
We retrospectively reviewed the medical records of hemodialysis patients treated with vancomycin or daptomycin at the Aichi Medical University Hospital from July 2014 to October 2019. Patients were excluded from the study for the following reasons: (1) patients were younger than 18 years of age, (2) patients received less than twice of vancomycin or daptomycin administration, and (3) patients switched from vancomycin to daptomycin (or vice versa). The study was reviewed and approved by the ethics committee of the Aichi Medical University (No. 2020-058).
4.2. Treatment Regimen
Vancomycin was administered to achieve a target trough of 10–20 mg/L on the day of the second hemodialysis according to Japanese therapeutic drug monitoring guidelines [
25]. Daptomycin was administered thrice per week according to daptomycin prescription information (4–6 mg/kg/day). Some of the patients received a dose of 4–6 mg/kg daptomycin thrice per week with a loading dose (>8 mg/kg) on day 1 based on our previous study results [
17,
23].
4.3. Data Collection
At least 3 days before the start of treatment, treatment data, including patient demographics, hospitalization history, source of infection, and laboratory data, were retrospectively collected through chart review. The clinical outcomes and antibiotic-related adverse reactions were recorded for each patient.4.4. Microbiological Data
Identification and susceptibility tests for the isolated organisms were conducted at the Department of Laboratory at Aichi Medical University Hospital. All isolates were susceptibility-tested using the broth microdilution method as described by the Clinical and Laboratory Standards Institute (CLSI) [
26]. Vancomycin-resistant pathogens were defined as isolates with an MIC of >4 mg/L for
Staphylococcus and >8 mg/L for
Enterococcus. Daptomycin-resistant pathogens were defined as isolates with an MIC > 2 mg/L for
Staphylococcus and >4 mg/L for
Enterococcus. For the purpose of this study, all specimens (blood, wound, abscess, pus, or tissue) cultured at the microbiology laboratory during the study periods were included.
4.4. Clinical and Microbiological Effectiveness
The evaluation was performed in accordance with previous studies [
17,
22]. Data regarding inflammatory markers of body temperature and C-reactive protein (CRP) level at least 3 days before the start (baseline level) and after the end of antibiotic treatment were collected. For clinical effectiveness, we evaluated the percentages of patients who reached a body temperature <37.0 °C and CRP <60% of the baseline level. Survival was defined as survival at 14 and 30 days after antibiotic treatment. A microbiological cure was defined as effective when bacteria disappeared during and after antibiotic treatment.
4.5. Safety Evaluation
We evaluated abnormality with CTCAE version 4.03 the Common Terminology Criteria for Adverse Events (CTCAE). The abnormality was defined as follows: aspartate aminotransferase (AST), >2 × upper baseline (35 U/L); alanine aminotransferase (ALT), >2 × upper baseline (30 U/L); creatinine kinase (CK), >1.3 × upper baseline (200 U/L); and eosinophil granulocyte count, >500/μL. In addition, we assessed the onset of eosinophilic pneumonia and rash (allergies).
4.6. Evaluation of Covariate Related to 30-Day Mortality
The following factors were compared between survival and non-survival groups: loading dose, initial vancomycin trough concentrations, microbiological effectiveness, bacteremia, and detection of vancomycin- or daptomycin-resistant pathogens, MRSA, MRCNS, and E. faecium. Moreover, logistic regression analysis was performed to determine the odds ratio (OR) for 30-day mortality. Factors showing a p-value of 0.1 were considered candidate predictors significantly related to mortality.
4.7. Evaluation of a Loading Dose of Daptomycin for Clinical Effectiveness and Safety
Previously, we revealed that receiving a loading dose of daptomycin was a significant covariate for mortality in hemodialysis patients [
23]. However, a logistic regression analysis showed that receiving a loading dose of daptomycin was identified as a positive covariate related to mortality. Thus, we compared the influence of daptomycin treatment with a loading dose of vancomycin and daptomycin treatment without a loading dose on clinical and microbiological outcomes in hemodialysis patients.
4.8. Statistical Analysis
The data regarding the clinical characteristics of the patients were expressed as median values (minimum–maximum). Statistical significance was evaluated using the chi-square test for categorical data and the unpaired t-test for continuous data. Statistical analysis was performed using JMP, version 10.0 (SAS, Tokyo, Japan). A p-value of <0.05 was required to achieve statistical significance.